Dataset Information

PetelenzKuehn_osmoadaptation_gpd1D

ABSTRACT: Petelenz-kurdzeil2013 - Osmo adaptation gpd1D This model is described in the article: Quantitative analysis of glycerol accumulation, glycolysis and growth under hyper osmotic stress. Petelenz-Kurdziel E, Kuehn C, Nordlander B, Klein D, Hong KK, Jacobson T, Dahl P, Schaber J, Nielsen J, Hohmann S, Klipp E. PLoS Comput. Biol. 2013; 9(6): e1003084 Abstract: We provide an integrated dynamic view on a eukaryotic osmolyte system, linking signaling with regulation of gene expression, metabolic control and growth. Adaptation to osmotic changes enables cells to adjust cellular activity and turgor pressure to an altered environment. The yeast Saccharomyces cerevisiae adapts to hyperosmotic stress by activating the HOG signaling cascade, which controls glycerol accumulation. The Hog1 kinase stimulates transcription of genes encoding enzymes required for glycerol production (Gpd1, Gpp2) and glycerol import (Stl1) and activates a regulatory enzyme in glycolysis (Pfk26/27). In addition, glycerol outflow is prevented by closure of the Fps1 glycerol facilitator. In order to better understand the contributions to glycerol accumulation of these different mechanisms and how redox and energy metabolism as well as biomass production are maintained under such conditions we collected an extensive dataset. Over a period of 180 min after hyperosmotic shock we monitored in wild type and different mutant cells the concentrations of key metabolites and proteins relevant for osmoadaptation. The dataset was used to parameterize an ODE model that reproduces the generated data very well. A detailed computational analysis using time-dependent response coefficients showed that Pfk26/27 contributes to rerouting glycolytic flux towards lower glycolysis. The transient growth arrest following hyperosmotic shock further adds to redirecting almost all glycolytic flux from biomass towards glycerol production. Osmoadaptation is robust to loss of individual adaptation pathways because of the existence and upregulation of alternative routes of glycerol accumulation. For instance, the Stl1 glycerol importer contributes to glycerol accumulation in a mutant with diminished glycerol production capacity. In addition, our observations suggest a role for trehalose accumulation in osmoadaptation and that Hog1 probably directly contributes to the regulation of the Fps1 glycerol facilitator. Taken together, we elucidated how different metabolic adaptation mechanisms cooperate and provide hypotheses for further experimental studies. This model is hosted on BioModels Database and identified by: BIOMD0000000610. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

SUBMITTER: Clemens Kühn

PROVIDER: BIOMD0000000610 | BioModels | 2016-04-20

REPOSITORIES: BioModels

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Quantitative analysis of glycerol accumulation, glycolysis and growth under hyper osmotic stress.

Petelenz-Kurdziel Elzbieta E Kuehn Clemens C Nordlander Bodil B Klein Dagmara D Hong Kuk-Ki KK Jacobson Therese T Dahl Peter P Schaber Jörg J Nielsen Jens J Hohmann Stefan S Klipp Edda E

PLoS computational biology 20130606 6

We provide an integrated dynamic view on a eukaryotic osmolyte system, linking signaling with regulation of gene expression, metabolic control and growth. Adaptation to osmotic changes enables cells to adjust cellular activity and turgor pressure to an altered environment. The yeast Saccharomyces cerevisiae adapts to hyperosmotic stress by activating the HOG signaling cascade, which controls glycerol accumulation. The Hog1 kinase stimulates transcription of genes encoding enzymes required for gl ...[more]

PMID: 23762021

Publication: 1/5

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Project description:Schaber2012 - Hog pathway in yeast The high osmolarity glycerol (HOG) pathway in the yeast Saccharomyces cerevisiae is one of the best-studied mitogen-activated protein kinase (MAPK) pathways and serves as a prototype signalling system for eukaryotes. This pathway is necessary and sufficient to adapt to high external osmolarity. A key component of this pathway is the stress-activated protein kinase (SAPK) Hog1, which is rapidly phosphorylated by the SAPK kinase Pbs2 upon hyper-osmotic shock, and which is the terminal kinase of two parallel signalling pathways, subsequently called the Sho1 branch and the Sln1 branch, respectively. Ensemble modelling (192 models) is used to study the yeast HOG pathway, a prototype for eukaryotic mitogen-activated kinase signalling systems. The best fit model (Model Nr.22: described here) provides new insights into the function of this system, some of which are then experimentally validated. This model is described in the article: Modelling reveals novel roles of two parallel signalling pathways and homeostatic feedbacks in yeast. Schaber J, Baltanas R, Bush A, Klipp E, Colman-Lerner A. Mol Syst Biol. 2012 Nov 13;8:622. Abstract: The high osmolarity glycerol (HOG) pathway in yeast serves as a prototype signalling system for eukaryotes. We used an unprecedented amount of data to parameterise 192 models capturing different hypotheses about molecular mechanisms underlying osmo-adaptation and selected a best approximating model. This model implied novel mechanisms regulating osmo-adaptation in yeast. The model suggested that (i) the main mechanism for osmo-adaptation is a fast and transient non-transcriptional Hog1-mediated activation of glycerol production, (ii) the transcriptional response serves to maintain an increased steady-state glycerol production with low steady-state Hog1 activity, and (iii) fast negative feedbacks of activated Hog1 on upstream signalling branches serves to stabilise adaptation response. The best approximating model also indicated that homoeostatic adaptive systems with two parallel redundant signalling branches show a more robust and faster response than single-branch systems. We corroborated this notion to a large extent by dedicated measurements of volume recovery in single cells. Our study also demonstrates that systematically testing a model ensemble against data has the potential to achieve a better and unbiased understanding of molecular mechanisms. This model is hosted on BioModels Database and identified by: MODEL1209110001 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Transcriptome analyses using a wild-type strain of Saccharomyces cerevisiae were performed to assess the overall pattern of gene expression during the transition from glucose-based fermentative to glycerol-based respiratory growth. These experiments revealed a complex suite of metabolic and structural changes associated with the adaptation process. Alterations in gene expression leading to remodeling of various membrane transport systems and the cortical actin cytoskeleton were observed. Transition to respiratory growth was accompanied by alterations in transcript patterns demonstrating not only a general stress response, as seen in earlier studies, but also the oxidative and osmotic stress responses. In some contrast to earlier studies, these experiments identified modulation of expression for many genes specifying transcription factors during the transition to glycerol-based growth. Importantly and unexpectedly, an ordered series of changes was seen in transcript levels from genes encoding components of the TFIID, SAGA (Spt-Ada-Gcn5-Acetyltransferase), and SLIK (Saga LIKe) complexes and all three RNA polymerases, suggesting a modulation of structure for the basal transcriptional machinery during adaptation to respiratory growth. In concert with data given in earlier studies, the results presented here highlight important aspects of metabolic and other adaptations to respiratory growth in yeast that are common to utilization of multiple carbon sources. Importantly, they also identify aspects specific to adaptation of this organism to growth on glycerol as sole carbon source. A time-series illustrating the transition from fermentation using glucose (dextrose) as sole carbon source to respiration using glycerol as sole carbon source. Time points of 15 minutes, 30 minutes and 60 minutes as well as growth on dextrose, glycerol or ethanol as sole carbon source from a starter culture. Three biological replicates of the 30 minute time point and growth on glycerol from starter culture.

Dataset Information

PetelenzKuehn_osmoadaptation_gpd1D

Publications

Quantitative analysis of glycerol accumulation, glycolysis and growth under hyper osmotic stress.

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